The present invention relates to the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide, better known under its international generic trade name "Minoxidil".
"Minoxidil" is known for its antihypertensive properties and for its application in the treatment of alopecia.
Several processes for the preparation of 6-piperidino-2,4-diaminopyrimidine-3-oxide are already known. U.S. Pat. No. 3,382,247 describes a process which consists in preparing, in a first stage, 6-chloro-2,4-diamino pyrimidine from 6-hydroxy-2,4-diaminopyrimidine by treatment with phosphorus oxychloride. Reaction of a phenolate on 6-chloro-2,4-diaminopyrimidine produces 6-phenoxy-2,4-diaminopyrimidine. This latter is oxidized to the corresponding 3-nitro-oxide by metachloroperbenzoic acid (MCPA). After reaction with piperidine, "Minoxidil" is isolated.
GB-A-No. 2 032 434 describes a process for the preparation of "Minoxidil" consisting in preparing, in a first stage, the O-tosylate of 6-hydroxy-2,4-diamino pyrimidine, oxidizing the latter to a corresponding oxide by the action of MCPA and finally treating the tosylate N-oxide with piperidine.
According to U.S. Pat. No. 3,910,928 the pyrimidine ring is synthesized from 3-cyaniminopropionitrile.
In the first two syntheses the amine groups in the 2- and 4-positions of the chloro- or hydroxy diaminopyrimidine remain free. p The applicant has discovered a novel process for the preparation of 6-piperidino- 2,4-diaminopyrimidine- 3-oxide or "Minoxidil", following a simple and less onerous procedure when compared with state of the art processes. This process forms one object of the invention.
Thus one object of the invention is a novel process for the preparation of "Minoxidil".
Another object of the invention is novel products prepared during this process.
Further objects of the invention will become apparent from the following description and examples.
In one aspect, the invention consists in a process for the preparation of 6-piperidino-2,4-diamino pyrimidine-3-oxide wherein, in a first stage, at least one of the amino groups of a compound having formula 1: ##STR2## where X represents a halogen atom or OH group, is protected by an isocyanate having formula: EQU R--N.dbd.C.dbd.O
where R represents an alkyl group preferably having 1 to 6 carbon atoms, with one of the amino groups of the compound having formula (1); addition resulting in a urea derivative which is subsequently oxidized to transform it into the corresponding N-oxide, said N-oxide then being reacted with piperidine then undergoing an elimination reaction to remove the protective group(s) by treatment with an organic or inorganic base.
In another aspect the invention consists in a novel compound having the formula: ##STR3## wherein:
X represents OH,Cl,O-tosyl,O-benzenesulfonyl;
R.sub.1 and R.sub.2 are independent of each other and represent a hydrogen atom or the group RNHCO-, where R represents a C.sub.1 to C.sub.6 alkyl, and R.sub.1 and R.sub.2 do not simultaneously represent hydrogen; and
n equals 0 or 1,
including their tautomeric or isomeric forms.